Microparticle drug carriers including liposomal drug as typical examples and polypeptides such as protein drug are known to have poor retention in blood and be easily captured by the reticuloendothelial system (hereinafter abbreviated as “RES”) such as liver and spleen when they are intravenously administered. The presence of RES is a serious obstacle when a microparticle drug carrier is utilized as a targeting type preparation, which delivers a medicament to organs other than RES, and as a sustained-release preparation, which allows a medicament retained in blood for a long period of time to control the release of the medicament.
Researches have so far been conducted to impart a microcirculation property to the aforementioned preparations. Some proposals have been made, including, for example, a method of maintaining a high blood concentration by reducing a size of liposomes in view of relative easiness of a control of physicochemical properties of lipid bilayers of liposomes (Biochimica et Biophysica Acta, Vol. 761, p. 142, 1983), a method of utilizing lecithin having a high phase transfer temperature (Biochemical Pharmacology, Vol. 32, p. 3381, 1983), a method of utilizing sphingomyelin instead of lecithin (Biochemical Pharmacology, Vol. 32, p. 3381, 1983), a method of adding cholesterol as a membrane component of liposomes (Biochimica et Biophysica Acta, Vol. 761, p. 142, 1983) and the like. However, by applying the aforementioned method, no work has been known so far that successfully provides a microparticle drug carrier having favorable retention in blood and being hardly taken up by RES.
As another approach for solution, researches have been made for providing a microcirculation property and escapability from RES by modification of membrane surfaces of liposomes with a glycolipid, glycoprotein, amino acid-lipid, polyethylene glycol-lipid or the like. Substances for the modification so far reported include, for example, glycophon (The Pharmaceutical Society of Japan, the 106th Annual Meeting, Summaries of Symposia, p.336, 1986), ganglioside GM1 (FEBS Letters, Vol. 223, p.42, 1987), phosphatidylinositol (FEBS Letters, Vol. 223, p.2, 1987), glycophon and ganglioside GM3 (Japanese Patent Unexamined Publication (Kokai) No. 63-22 1837), polyethylene glycol derivative (FEBS Letters, Vol. 268, p.235, 1990), glucuronic acid derivative (Chemical & Pharmaceutical Bulletin, Vol. 38, p. 1633, 1990), glutamic acid derivative (Biochimica et Biophysica Acta, Vol. 1108, p.257, 1992), polyglycerin phospholipid derivative (Japanese Patent Unexamined Publication No. 6-2280 12), and the like.
As the modification of a polypeptide, introduction of two water-soluble polymer molecules into a polypeptide by using triazine has been reported for a purpose of decreasing the number of binding sites of the polypeptide and thereby increasing a residual amount of active groups such as lysine residues in the polypeptide. Also as for a liposome preparation, introduction of two water-soluble polymer molecules into triazine to increase the molecular weight of the water-soluble polymer, and modification of liposome surfaces by using the resulting polymer is reported. However, when a water-soluble polymer is introduced by using triazine, only two water-soluble polymers can be introduced into the triazine ring. Therefore, it is necessary to add a large amount of a compound, which contains two water-soluble polymers introduced in triazine, to increase the number of the water-soluble polymer chains on liposome surfaces. Further, a compound consisting of two or three polyalkylene glycol chains bonded with one functional group has been reported as a polymer modifier. However, the number of the polymer chains, for which this modification can be applied, is limited to 2 or 3, and the aforementioned compound cannot have more than one functional group, because the ends of the polyalkylene glycol chains, except for one end, are blocked with methyl group or ethyl group. It is expected that the effect of this compound to impart microcirculation property to liposome surfaces is inferior to that of a compound having a hydrophilic group. Furthermore, although phospholipid derivatives containing a polyalkylene oxide group have also been used also as surfactants, no compound has been known so far that is safe for living bodies and can be stably used under a condition of a high salt concentration.